Process For the Preparation of Enantiomerically Pure1-Substitued-3-Aminoalcohols

ABSTRACT

A process for the preparation of enantiomerically pure 1-substituted-3-amino-alcohols, particularly of (S)-(−)- and (R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol, by asymmetrically hydrogenating salts of a carboxylic acids with an aminoketone of the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is 2-thienyl, 2-furanyl or phenyl, each optionally substituted with one or more halogen atoms and/or one or more C 1-4 -alkyl or C 1-4 -alkoxy groups, and wherein R 2  is C 1-4 -alkyl or phenyl, each optionally substituted with one or more halogen atoms and/or one or more C 1-4 -alkyl or C 1-4 -alkoxy groups. The corresponding aminoalcohols are obtained by subsequent hydrolysis of their salts. Salts of a carboxylic acid with the aminoketones and the aminoalcohols obtained by asymmetrically hydrogenating the aminoketones, respectively.

The present invention refers to a process for the preparation ofenantiomerically pure 1-substituted-3-aminoalcohols, particularly of(S)-(−)- and (R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol, which canbe obtained by asymmetrically hydrogenating salts of the correspondingaminoketones and a carboxylic acid, particularly of3-N-methylamino-1-(2-thienyl)-1-propanone and a carboxylic acid, in thepresence of a catalyst comprising a transition metal and a diphosphineligand.

(S)-(−)-3-N-Methylamino-1-(2-thienyl)-1-propanol is an intermediate forthe preparation of(S)-(+)-methyl-[3-(1-naphthyloxy)-3-(2-thienyl)-propyl]-amine(duloxetine), an agent for the treatment of depression and urinaryincontinence (Huiling et al. Chirality 2000, 12, 26-29, Sorbera et al.Drugs of the Future 2000, 25(9), 907-916).

Several processes for racemic (WO2004/005239) and asymmetric (Sorbera etal. below) hydrogenation of thienyl aminoketone are known, as well asprocesses for chiral resolution of the resulting3-N-methylamino-1-(2-thienyl)-1-propanol (WO-A 2004/005220, WO-A2004/005307). Furthermore, processes for direct asymmetric hydrogenationusing transition metal-ligand complexes are disclosed in EP-A 0 647 648,EP-A 0 926 152, EP-A 0 945 457, EP-A 0 955 303 and WO-A 02/40492.

Huiling et al. describe a preparation of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol from thiophene.Thiophene is converted with 3-chloropropanoyl chloride in the presenceof tin tetrachloride in benzene to 3-chloro-1-(2-thienyl)-1-propanone,which is reduced with sodium borohydride in ethanol to3-chloro-1-(2-thienyl)-1-propanol. Kinetic resolution bytransesterification using vinyl butanoate and lipase B from Candidaantarctica as catalyst in hexane yielded(S)-3-chloro-1-(2-thienyl)-1-propanol, which is converted to(S)-3-iodo-1-(2-thienyl)-1-propanol using sodium iodide in acetone.Subsequent treatment with methylamine in tetrahydrofuran afforded(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol.

Sorbera et al. describe another preparation of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol from thiophene, whichis essentially the same as the one described by Huiling et al. exceptthat 3-chloro-1-(2-thienyl)-1-propanone is asymmetrically reduced to(S)-3-chloro-1-(2-thienyl)-1-propanol using borane and catalytic amountsof(R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborolein THF. This asymmetric reduction afforded(S)-3-chloro-1-(2-thienyl)-1-propanol in a yield of 86% from3-chloro-1-(2-thienyl)-1-propanone (Wheeler et al. J Label. Compd.Radiopharm. 1995, 36, 213-223).

The drawbacks of the preparations of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol above, are the use oftoxic or carcinogenic compounds such as tin tetrachloride and benzeneand/or the use of expensive compounds such as borane or sodium iodide,the latter being in addition difficult to dispose of. The disclosedasymmetric hydrogenation processes with diphosphines are not satisfyingin regard of the hydrogenation of3-N-methylamino-1-(2-thienyl)-1-propanone.

It is an object of the present invention to provide an ecological andeconomical process for the preparation of enantiomerically pure1-substituted-3-aminoalcohols, particularly of (S)-(−)- and(R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol. It is another objectof the present invention to provide new salts of3-N-methylamino-1-(2-thienyl)-1-propanone and organic acids.

These objects are achieved by the process of claim 1.

Provided is a process for the preparation of salts of a carboxylic acidwith an aminoalcohol of the formula

wherein R¹ is selected from the group consisting of 2-thienyl, 2-furanyland phenyl, each optionally substituted with one or more halogen atomsand/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and wherein R² isC₁₋₄-alkyl or phenyl, each optionally substituted with one or morehalogen atoms and/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups,comprising asymmetrically hydrogenating a salt of a carboxylic acid withan aminoketone of the formula

wherein R¹ and R² are as defined above,in the presence of a transition metal complex of a diphosphine ligand.

In Sakuraba et al., Chem. Pharm. Bull. 1995, 43, 748-753, and JP-A50-70412 the asymmetric hydrogenation of HCl salts of3-N-methylamino-1-phenyl-1-propanol and 3-amino-1-phenyl-1-propanone isdisclosed. EP-A-457559 discloses the preparation of HCl salts of3-dimethyl-amino-1-(2-thienyl)-1-propanone and(S)-(−)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropane-amine as well as theoxalate salts of(S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-propanamine and(S)-(−)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine. Thelatter two ones being aromatic ethers of the compounds of formula I.Direct preparation of the respective organic acid salts is not disclosedin the prior art. Surprisingly, these compounds can be used in thehydrogenation reaction as well without increasing the amount ofby-products. Using organic acids is favourable, since they are lessacidic than HCl and therefore the risk of decomposition whileconcentrating during recovery of the products is reduced. The compoundsobtainable by the present process can be used directly without exchangeof the anion.

In a preferred embodiment, the diphosphine ligand is

(R,R,S,S)-“TangPhos”.

Asymmetric hydrogenation of 1-substituted-3-N-alkylamino-1-propanonehydrochlorides with diphosphine-transition metal complexes is notpossible without generating the free amines by neutralizing the acidicsalts. Due to the fact that the free1-substituted-3-N-alkylamino-1-propanones tend to decompose, theresulting 1-substituted-3-N-alkylamino-1-propanols are contaminated withby-products. Exchanging the hydrochloric acid with a carboxylic acidallows direct hydrogenation of the resulting, optionally purified, saltof a 1-substituted-3-N-alkylmino-1-propanone in high yields, high purityand high enantiomeric excess (ee). Avoiding decomposition of the freeaminoketone in the presence of base is another advantageous feature ofthe present invention.

Carboxylic acids in the meaning of the present invention are carboxylicacids having one free carboxyl group which can form a salt with an aminocompound of formulae II and/or I. Particularly preferred carboxylicacids are monocarboxylic acids. Dicarboxylic or tricarboxylic acidswhich do not form an inner salt like fumaric, maleic or adipic acid tendto give unusable resinous precipitates. However, carboxylic acids whichform an inner salt and still have one free carboxy group are comprisedin the definition of carboxylic acids in the meaning of the presentinvention. Examples of said carboxylic acids having more than onecarboxy group, but having only one free carboxy group, are amino acidssuch as aspartic acid or glutamic acid.

In a preferred process, the carboxylic acid is selected from the groupconsisting of optionally substituted C₁₋₁₈-alkanoic acids and optionallysubstituted mono- and bicyclic aromatic acids.

In a preferred embodiment the carboxylic acids are substituted with oneor more C₁₋₆-alkyl, C₁₋₆-alkoxy, aryl, amino, optionally protectedcarbonyl, halogen or hydroxy groups and optionally further carboxylicgroups.

Examples for C₁₋₁₈-alkanoic acids in the meaning of the present processare butyric acid, valeric acid, caproic acid, pelargonic acid, lauricacid, palmitic acid, stearic acid, 2-hydroxybutyric acid,3-hydroxy-3-methylbutyric acid, 2-hydroxy-4-phenylbutyric acid,L-aspartic acid, D-aspartic acid, DL-aspartic acid, 2-keto-L-gulonicacid, 2-keto-D-gulonic acid,(−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid and(+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid.

In a further preferred process the carboxylic acid is a mono- orbicyclic aromatic acid, optionally substituted with one or moreC₁₋₆-alkyl, C₁₋₆-alkoxy, halogen or hydroxy groups.

Examples for mono- and bicyclic aromatic carboxylic acids in the meaningof the present process are benzoic acid, salicylic acid,3-methyl-benzoic acid and 1-, or 2-naphthalene-carboxylic acid.

Here and hereinbelow the term “enantiomerically pure compound” comprisesoptically active compounds with an enantiomeric excess (ee) of at least90%.

Here and hereinbelow the term “C_(1-n)-alkyl”, for example “C₁₋₆-alkyl”,represents a linear or branched alkyl group having 1 to n carbon atoms.Optionally with one or more halogen atoms substituted C₁₋₆-alkylrepresents for example methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl and hexyl.

Here and hereinbelow the term “″C_(1-n)-alkoxy”, for example“C₁₋₆-alkoxy”, represents a linear or branched alkoxy group having 1 ton carbon atoms. Optionally with one or more halogen atoms substitutedC₁₋₆-alkoxy represents for example methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.

Here and hereinbelow the term “C_(3-n)-cycloalkyl”, for example“C₃₋₁₀-cycloalkyl”, represents a cycloaliphatic group having 3 to ncarbon atoms. Optionally with one or more halogen atoms substitutedC₃₋₁₀-cycloalkyl represents for example mono- and polycyclic ringsystems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, adamantyl or norbornyl.

Here and hereinbelow the term “C_(3-n)-cycloalkoxy”, for example“C₃₋₁₀-cycloalkoxy” represents a cycloalkoxy group having 3 to n carbonatoms. Optionally with one or more halogen atoms substitutedC₃₋₁₀-cycloalkyl represents for example cyclopropoxy, cyclobutoxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy andcyclodecyloxy.

Here and hereinbelow the term “aryl” represents an aromatic group,preferably phenyl or naphthyl, optionally being substituted with one ormore halogen atoms, nitro and/or amino groups, and/or optionallysubstituted C₁₋₆-alkyl, C₁₋₆-alkoxy or di-C₁₋₆-alkylamino groups,wherein the alkyl moieties optionally are substituted with one or morehalogen atoms.

In a preferred embodiment R¹ is 2-thienyl, optionally substituted withone or more halogen atoms, and R² is methyl or ethyl.

In a further preferred embodiment, the compound of formula II isselected from the group consisting of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol,(S)-(−)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol,(R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol and(R)-(+)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol.

In a preferred process, the transition metal is selected from the groupconsisting of rhodium, ruthenium and iridium, preferably rhodium.

In a further preferred process, the diphosphine ligand is selected fromthe group consisting of

(S,S,S,S)-“Me-KetalPhos”, (S) and (R)-“MeO-BiPhep” and“(R_(P),R_(P),S_(C),S_(C))-DuanPhos”. All mentioned ligands arecommercially available, e.g. from Chiral Quest, Inc, Monmouth Junction,N.J., USA.

In a preferred process, the compounds of formulae Ia and Ib are obtainedfrom their corresponding salts with a carboxylic acid by aqueoushydrolysis in the presence of an alkali or earth alkali hydroxide.

Provided are salts of a carboxylic acid with an aminoketone of theformula

wherein R¹ is selected from the group consisting of 2-thienyl, 2-furanyland phenyl, each optionally substituted with one or more halogen atomsand/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and wherein R² isC₁₋₄-alkyl or phenyl, each optionally substituted with one or morehalogen atoms and/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups.

Particularly preferred, the carboxylic acid is selected from the groupconsisting of C₁₋₁₈-alkanoic acids,(−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid,(+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid, 2-keto-L-gulonicacid, 2-keto-D-gulonic acid, L-aspartic acid, D-aspartic acid, benzoicacid, 3-methylbenzoic acid, salicylic acid and 2-naphthalenecarboxylicacid.

Furthermore provided are salts of a carboxylic acid with an aminoalcoholof the formula

wherein R¹ is selected from the group comprising 2-thienyl, 2-furanyland phenyl, each optionally substituted with one or more halogen atomsand/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and wherein R² isC₁₋₄-alkyl or phenyl, each optionally substituted with one or morehalogen atoms and/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups, withthe exception of salts wherein the acid is(−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid or(+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid.

The present invention is illustrated by the following non-limitingexamples.

EXAMPLES Example 1 Preparation of3-N-methylamino-1-(2-thienyl)-1-propanone hydrochloride (PRON—HCl)

A mixture of 2-acetylthiophene (25.5 g, 200 mmol), methylaminehydrochloride (14.9 g, 220 mmol), paraformaldehyde (8.2 g, 280 mmol) andethanol (100 mL) is heated in an autoclave at 120 to 130° C. for 9 h.The obtained light brown solution is cooled to 20° C. and part of theethanol (50 mL) is removed by distillation in vacuo. Ethyl acetate (200mL) is added to the residue to afford a thick suspension, which iscooled to 0° C. and kept for 45 min at that temperature. The obtainedprecipitate is isolated by filtration and dried, yielding 29.3 g3-N-methylamino-1-(2-thienyl)-1-propanone hydrochloride (PRON—HCl, 71%)as a slightly yellow powder.

Comparative Example 1 Preparation of racemic3-N-methylamino-1-(2-thienyl)-1-propanol (PROL-HCl)

Sodium hydroxide (4.0 g of a 50% aqueous solution) is added to a mixtureof PRON—HCl (10.3 g, 50 mmol) and ethanol (35 mL) at 4° C. in about 5min. Neat sodium borohydride (0.95 g, 25 mmol) is added in severalportions in about 30 min to afford a beige suspension which is stirredat 4° C. for additional 4 h. Acetone (10 mL) is added dropwise in 5 minand the mixture is stirred for additional 10 min before water (20 mL) isadded. The mixture is concentrated about 5 times in vacuo and theobtained residue is extracted with tert-butyl methyl ether (MTBE) (2×20mL). The collected organic phases are concentrated in vacuo affording7.2 g racemic 3-N-methylamino-1-(2-thienyl)-1-propanol (PROL-HCl 84%) asan orange oil which crystallizes spontaneously after a few h. ¹H-NMR(DMSO-d₆, 400 MHz): 7.35 (1H, dd, J=4.8, 1.0), 6.94 (1H, dd, J=4.8,3.6), 6.90 (1H, dd, J=3.6, 1.0), 4.90 (1H, t), 3.7 (2H, m), 2.56 (2H,m), 2.25 (3H, s), 1.79 (2H, q); ¹³C-NMR (DMSO-d₆, 100 MHz): 150.9,126.3, 123.7, 122.3, 67.8, 48.5, 38.7, 36.0.

Comparative Example 2 Preparation of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol ((S)-PROL-HCl)

In a 50 mL autoclave a solution of PRON-HCl (250 mg, 0.56 mmol) inmethanol (5 mL) and an equivalent amount of NaOH mixture is chargedunder nitrogen. Afterwards, a solution of [Rh((S,S)-Me-Duphos)]BF₄ (2.7mg) in methanol (2 mL) prepared under nitrogen is added via a syringe.The autoclave is then closed and purged several times with nitrogen,heated up to 50° C., then hydrogen is added until the pressure reaches30 bar. After 5 h at that temperature under stirring, the autoclave iscooled to room temperature. Once cold, the clear yellow-brownishsolution is transferred into a 50 mL round bottom flask and concentratedto dryness affording a beige solid (0.23 g, 92%, ee: about 97% by HPLC).

Comparative Example 3 Preparation of (S)-PROL

A solution of PRON—HCl (250 mg, 0.56 mmol) in methanol (5 mL) is chargedunder nitrogen in a 50 mL autoclave. Afterwards, a solution of 1.8 mgRh(cod)₂BF₄ and 2.7 mg the ligand of formula III, with R³═OMe,R⁴═R⁵=dicyclohexylphosphinyl and R⁶═R⁷=diphenyl-phosphinyl, in methanol(2 mL) previously prepared by stirring the components for 15 min undernitrogen is added via a syringe. The hydrogenation is carried out asdescribed above, affording (S)-PROL as a beige solid (0.21 g, 84%, ee:about 11% by HPLC)

Example 2 Preparation of 3-N-methylamino-1-(2-thienyl)-1-propanone andits (−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid salt(PRON-diketegulac)

A mixture of PRON—HCl (15.0 g, 47.5 mmol), MTBE (170 mL) and water (20mL) is cooled to 0° C., then sodium hydroxide (12.8 g of a 20% aqueoussolution) is added dropwise in 15 min and stirred for 10 min.Afterwards, the stirring is stopped, the two phases are separated andthe organic one is washed with water (60 mL). Then the collected aqueousphases are extracted with MTBE (2×50 mL). To the two collected organiclayers is then added dropwise a solution of(−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid ((−)-DAG, 13.1 g,4.48 mol) in MTBE (400 mL). The product precipitates already duringaddition. At the end of the addition, the suspension is concentrated invacuo to half the volume, the residue is heated to 50 to 60° C. andheptane (250 mL) is added. Afterwards, the suspension is cooled down to5° C., the precipitate is filtered off and washed with MTBE/heptane(1:2, v:v, 2×60 mL). Drying at 30° C. for 15 h at 30 mbar affords awhite solid (13.2 g, 66%). (assay is 96.1 weight %, purity is 99.6 area%, by HPLC)

Example 3 Preparation of Pron-Diketegulac

A sticky suspension of 675 g (2.13 mol) PRON-HCl in 5.5 L MTBE and 0.9 Lwater is stirred at a temperature of 0 to 5° C. in a 10 L vessel. Within0.5 h 576 g (2.88 mol) of a 20% NaOH-solution are added and the reactionmixture is stirred for another 30 min at the same temperature. Afterphase separation and washing of the organic phase with water (1.3 L) andextracting the aqueous phase with MTBE (2×1.3 L), the combined organiclayers are cooled in a 10 L vessel to below 10° C. After addition of asolution of 590 g (−)-DAG (2.02 mol) within 15 min a yellowish mixtureis obtained and crystallization occurs spontaneously or after additionof a crystallization aid, such as a small crystal of the product. Afterfurther stirring for 2 h at 0 to 5° C., filtration, washing with MTBE(2×1.5 L) and drying in vacuo at 50 to 55° C., the product (740 g ofoff-white solid matter) is obtained.

Example 4 Recrystallization of PRON-diketegulac

A suspension of 738 g of the product of example 3, 5.3 L MTBE and 2.7 Lmethanol are heated under reflux. After addition of further 1.8 Lmethanol at the same temperature a clear yellowish solution is obtained.During cooling to 0 to 5° C. within 3 h, the product precipitates. Afterfurther stirring at 0 to 5° C. for 2 h, filtration, washing with MTBE(2×1 L) and drying in vacuo at 50 to 55° C., the product (538 g of whitesolid) is obtained.

Example 5 Hydrogenation of (S)-PRON-diketegulac

A solution of PRON-diketegulac of example 4 (250 mg, 0.56 mmol) inmethanol (5 mL) is charged under nitrogen in a 50 mL autoclave. Asolution of [Rh((R,R,S,S)-Tangphos)-(norbornadiene)]BF₄ (3 mg) inmethanol (2 mL) is added via a syringe to the first mixture. Thehydrogenation is carried out as described above, affording the salt of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol and (−)-DAG((S)-PROL-diketegulac) as a beige solid (0.22 g, 92%). Conversion is100% by HPLC, ee is 95% (S isomer id preferably formed).

Example 6 Hydrolysis of (S)-PROL-diketegulac

9.0 g (20.2 mmol) of solid PROL-diketegulac of example 5 is added inportions to a mixture of water (22 mL), CH₂Cl₂ (18 mL) and an aqueoussolution of sodium hydroxide (30%, 2.07 g, 25.9 mmol) and the reactionmixture (two phases) is stirred for 15 min. After phase separation, theaqueous phase is extracted with CH₂Cl₂ (12 mL). The combined organicphases are washed with water (13 mL). The solvent is removed at 20° C.in vacuo to a volume of 9 mL. Heptane (18 mL) is added to the residueand the resulting solution is further concentrated to about 18 mL invacuo at 20° C. Crystallization occurs spontaneously or after seedingand the sus-pension is further stirred for 30 min at 20° C. Theprecipitate is filtrated, washed with heptane (7 mL) and dried at 40° C.for 15 h at 25 mbar affording (S)-PROL (3.0 g of white solid, 87%).

Example 7 Preparation of PRON-2-keto-L-gulonate

A mixture of 15.0 g (47.5 mmol) PRON—HCl, 170 mL MTBE and 20 mL water iscooled to 5 to 10° C. in a 250 mL vessel. After addition of 12.8 g of a20% NaOH solution the mixture is stirred for further 15 min, while phaseseparation occurs. The organic phase is washed with water (60 mL) andthe aqueous phase is extracted with MTBE (2×50 mL). The combined organicphases are cooled to below 10° C. and within 15 min a suspension of 8.7g (45 mmol) 2-keto-L-gulonic acid in 400 mL MTBE is added. A stickysuspension is formed. The volume of the solvent is reduced toapproximately the half. The reaction mixture is heated under reflux and250 mL heptane are added. After further addition of 300 mL methanol andheating under reflux for 30 min, the mixture is cooled to roomtemperature (RT) and the solvent is removed. The resinous residue ismixed with 100 mL methanol and the solid matter is filtered off anddried in vacuo at 50 to 55° C. to yield 8.3 g tan solid matter.

Example 8 Recrystallization of PRON-2-keto-L-gulonate

8.2 g solid product of example 7 is heated under reflux with 100 mLethanol. Under stirring, the clear solution is cooled to RT and a resindeposits. The mixture is stirred for 1 hour at RT. The moist resin isdried in vacuo at 50 to 55° C. to afford 4.5 g of tan solid matter.

Example 9 Preparation of Pron-Benzoate

A mixture of 15.0 g (47.5 mmol) PRON-HCl, 170 mL MTBE and 20 mL water iscooled to 5 to 10° C. in a 250 mL vessel. After addition of 12.8 g of a20% NaOH solution the mixture is stirred for further 15 min, while phaseseparation occurs. The organic phase is washed with water (60 mL) andthe aqueous phase is extracted with MTBE (2×50 mL). The combined organicphases are cooled to below 10° C. and within 15 min a suspension of 5.5g (45 mmol) benzoic acid in 400 mL MTBE is added. An oily suspension isformed. The volume of the solvent is reduced to approximately the half.The reaction mixture is heated under reflux and 250 mL heptane areadded. The mixture is cooled to RT and stirred for 1 hour. The solidmatter is filtered off, washed with Heptane/MTBE (2×60 mL) and dried invacuo at 50 to 55° C. Yield: 10.4 g yellow-brown solid product.

Example 10 Recrystallization of PRON-benzoate

10.3 g solid product of example 9 is heated under reflux with 50 mLethylacetate. Under stirring, the clear solution is cooled to RT and asolid deposits. The mixture is stirred for 1 hour at RT. The resin isdried in vacuo at 50 to 55° C. which affords 6.1 g of light tan solidmatter.

Example 11 Hydrogenation of PRON-benzoate

A solution of PRON-benzoate of example 10 (146 mg) in methanol (5 mL) ischarged under nitrogen in a 50 mL autoclave. Afterwards, a solution of 3mg [Rh((S,S)-Me-Duphos)-(1,4-cyclooctadiene)]BF₄ in methanol (2 mL) isadded via a syringe. The mixture is hydrogenated as described aboveaffording 0.12 g solid product ((S)-PROL-benzoate). Conversion is 99% byHPLC, ee is 96.7%, S isomer preferably formed.

Comparative Example 4 Preparation of PRON-p-toluenesulfonate

A mixture of 15.0 g (47.5 mmol) PRON—HCl, 170 mL MTBE and 20 mL water iscooled to 5 to 10° C. in a 250 mL vessel. After addition of 12.8 g of a20% NaOH solution the mixture is stirred for further 15 min, while phaseseparation occurs. The organic phase is washed with water (60 mL) andthe aqueous phase is extracted with MTBE (2×50 mL). The combined organicphases are cooled to below 10° C. and within 15 min a suspension of 8.6g (45 mmol) p-toluenesulfonic acid monohydrate in 400 mL MTBE is added.An oily suspension is formed. The volume of the solvent is reduced toapproximately the half. The reaction mixture is heated under reflux and250 mL heptane are added. The mixture is cooled to RT and stirred for 30min. The solid matter is filtered off, washed with MTBE (2×60 mL) anddried in vacuo at 50 to 55° C. affording 14.3 g of product (tan solidmatter).

Comparative Example 5 Recrystallization of PRON-p-toluenesulfonate

14.2 g solid product of comparative example 4 is heated under refluxwith 50 mL isopropanol. Under stirring, the clear solution is cooled toRT and a solid deposits. The mixture is stirred for 1 hour at RT. Theresin is dried in vacuo at 50 to 55° C. which affords 12.5 g of tansolid matter.

Comparative Example 6 Hydrogenation of PRON-p-toluenesulfonate

A solution of PRON-p-toluenesulfonate of comparative example 5 (155 mg)in methanol (5 mL) is charged under nitrogen in a 50 mL autoclave.Afterwards, a solution of 3 mg [Rh(Me-Duphos)(1,4-cyclooctadiene)]BF₄ inmethanol (2 mL) is added via a syringe. The hydrogenation is carried outas described above, affording 0.12 g solid product((S)-PROL-p-toluenesulfonate). Conversion is 5% by HPLC, ee is >90%, Sisomer preferably formed.

Example 12 Preparation of Pron-Laurate

A mixture of 15.0 g (47.5 mmol) PRON-HCl, 170 mL MTBE and 20 mL water iscooled to 5 to 10° C. in a 250 mL vessel. After addition of 12.8 g of a20% NaOH solution the mixture is stirred for further 15 min, while phaseseparation occurs. The organic phase is washed with water (60 mL) andthe aqueous phase is extracted with MTBE (2×50 mL). The combined organicphases are cooled to below 10° C. and within 15 min a suspension of 9.0g (45 mmol) dodecanoic acid in 200 mL MTBE is added. After 1 hourstirring no product has solidified. The solvent is removed in vacuo andthe oily residue is solved in 50 mL acetonitrile and heated underreflux. The mixture is cooled to RT and stirred for 30 min. At first anoil secretes, which crystallizes at a temperature of below 30° C. Thesuspension is further stirred for 30 min at RT, than 30 mL acetonitrileare added to the thickened suspension. The solid matter is filtered off,washed with cold acetonitrile (2×10 mL) and dried in vacuo at below 30°C., affording 10.9 g product. Yield: 10.9 g white solid matter.

Example 13 Recrystallization of PRON-laurate

10.7 g solid product of example 12 is heated under reflux with 70 mLacetonitrile. Under stirring, the clear solution is cooled to RT and anoil secrets, which crystallizes at below 30° C. The mixture is stirredfor 30 min at 10 to 15° C. and 30 mL acetonitrile are added to thethickened suspension. The solid matter is filtered off, washed with coldacetonitrile (2×20 mL) and dried in vacuo at below 30° C. Yield: 6.3 gwhite solid matter.

Example 14 Hydrogenation of PRON-laurate

A solution of PRON-laurate of example 13 (184 mg) in methanol (5 mL) ischarged under nitrogen in a 50 mL autoclave. Afterwards, a solution of 3mg [Rh((R,R,S,S)-Tang-phos)(norbornadiene)]BF₄ in methanol (2 mL) isadded via a syringe. The mixture is hydrogenated as described above,affording 0.16 g solid product ((S)-PROL-laurate). Conversion is 100% byHPLC, ee is 93.6%, S isomer preferably formed.

1: A process for the preparation of salt of a carboxylic acid with anaminoalcohol of formula:

wherein R¹ is selected from the group consisting of 2-thienyl, 2-furanyland phenyl, each optionally substituted with one or more halogen atomsand/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups, and wherein R² isC₁₋₄-alkyl or phenyl, each optionally substituted with one or morehalogen atoms and/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxy groups,comprising asymmetrically hydrogenating a salt of a carboxylic acid withan aminoketone of formula:

wherein R¹ and R² are as defined above, in the presence of a transitionmetal complex of a diphosphine ligand. 2: The process of claim 1,wherein the carboxylic acid is selected from the group consisting ofoptionally substituted C₁₋₁₈-alkanoic acids and optionally substitutedmono- and bicyclic aromatic acids. 3: The process of claim 2, wherein R¹is 2-thienyl, optionally substituted with one or more halogen atoms, andR² is methyl or ethyl. 4: The process of claim 3, wherein the compoundof formula II is selected from the group consisting of(S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol,(S)-(−)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol,(R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol and(R)-(+)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol. 5: Theprocess of any of claim 4, wherein the transition metal is selected fromthe group consisting of rhodium, ruthenium or iridium. 6: The process ofany of claim 7, wherein the diphosphine ligand is selected from thegroup consisting of:

(S,S,S,S)-“Me-KetalPhos”, (S) and (R)-“MeO-BiPhep”, and“(R_(P),R_(P),S_(C),S_(C))-DuanPhos”. 7: The process of any of claim 6,wherein the compound of formulae Ia and/or Ib is obtained from itscorresponding salt with a carboxylic acid by hydrolysis in the presenceof an alkali metal hydroxide or an alkaline earth hydroxide. 8: A saltof a carboxylic acid with an aminoketone of the formula:

wherein R¹ is 2-thienyl or 2-furanyl, each optionally substituted withone or more halogen atoms and/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxygroups, and wherein R² is C₁₋₄-alkyl or phenyl, each optionallysubstituted with one or more halogen atoms and/or one or more C₁₋₄-alkylor C₁₋₄alkoxy groups. 9: The salt of claim 8, wherein the acid isselected from the group consisting of C₁₋₁₈-alkanoic acids,(−)-2,3:4,6-di-O-isopropyl-idene-2-keto-L-gulonic acid,(+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid, 2-keto-L-gulonicacid, 2-keto-D-gulonic acid, L-aspartic acid, D-aspartic acid,DL-aspartic acid, benzoic acid, 3-methyl-benzoic acid, salicylic acidand, 1-naphthalenecarboxylic acid and 2-naphthalenecarboxylic acid. 10:A salt of a carboxylic acid with an aminoalkohol of the formula:

wherein R¹ is 2-furanyl or phenyl, each optionally substituted with oneor more halogen atoms and/or one or more C₁₋₄-alkyl or C₁₋₄-alkoxygroups, and wherein R² is C₁₋₄-alkyl or phenyl, each optionallysubstituted with one or more halogen atoms and/or one or more C₁₋₄-alkylor C₁₋₄-alkoxy groups, with the exception of salts, wherein the acid is(−)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid or(+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid. 11: The processof claim 1, wherein the transitional metal complex of a diphosphineligand is a transitional metal complex of an aryldiphosphine ligand or abiaryldiphosphine ligand. 12: The process of claim 1, wherein R¹ is2-thienyl, optionally substituted with one or more halogen atoms, and R²is methyl or ethyl. 13: The process of claim 1, wherein the transitionmetal is rhodium. 14: The process of claim 1, wherein the diphosphineligand is selected from the group consisting of:

(S,S,S,S)-“Me-KetalPhos”, (S) and (R)-“MeO-BiPhep”, and“(R_(P),R_(P),S_(C),S_(C))-DuanPhos”. 15: The process of claim 1,wherein the compound of formulae Ia and/or Ib is obtained from itscorresponding salt with a carboxylic acid by hydrolysis in the presenceof an alkali metal hydroxide or an alkaline earth hydroxide.